tbuckley/cabot-search huggingface dataset:
Epigenetic regulator genes direct lineage switching in <i>MLL/AF4</i> leukemia
Authors: Ricky Tirtakusuma, Katarzyna Szoltysek, Paul Milne, Vasily V. Grinev, Anetta Ptasinska, Paulynn S. Chin, Claus Meyer, Sirintra Nakjang, Jayne Y. Hehir-Kwa, Daniel Williamson, Pierre Cauchy, Peter Keane, Salam A. Assi, Minoo Ashtiani, Sophie G. Kellaway, Maria R. Imperato, Fotini Vogiatzi, Elizabeth K. Schweighart, Shan Lin, Mark Wunderlich, Janine Stutterheim, Alexander Komkov, Elena Zerkalenkova, Paul Evans, Hesta McNeill, Alex Elder, Natalia Martinez-Soria, Sarah E. Fordham, Yuzhe Shi, Lisa J. Russell, Deepali Pal, Alex Smith, Zoya Kingsbury, Jennifer Becq, Cornelia Eckert, Oskar A. Haas, Peter Carey, Simon Bailey, Roderick Skinner, Natalia Miakova, Matthew Collin, Venetia Bigley, Muzlifah Haniffa, Rolf Marschalek, Christine J. Harrison, Catherine A. Cargo, Denis Schewe, Yulia Olshanskaya, Michael J. Thirman, Peter N. Cockerill, James C. Mulloy, Helen J. Blair, Josef Vormoor, James M. Allan, Constanze Bonifer, Olaf Heidenreich, Simon Bomken
Journal: Blood (2022)

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.
Practical Considerations in Diagnosing and Managing Early-Onset GI Cancers
Authors: Melissa A. Lumish, Andrea Cercek
Journal: Journal of Clinical Oncology (2022)

The incidence of early-onset (EO) GI cancers occurring in individuals younger than age 50 years has been rising at an alarming rate over the past two decades. Although this rise in incidence among young patients correlates with increased rates of obesity, changes in diet, and alterations in the environment, the effects of these environmental factors on carcinogenesis, metastasis, and treatment response are unknown. Although several unique clinical trends exist among EO-GI cancers and their average-onset GI cancer counterparts, GI cancers are molecularly indistinct between younger and older patients, and no data support distinct treatment paradigms for patients with EO disease. The majority of EO-GI cancers are not explained by germline changes. There remains a critical need for further research to understand the pathogenesis and optimal management of EO-GI cancers. In addition, current screening strategies are not adequate to identify EO-GI cancers, and early biomarkers are needed. Specialized centers, with a focus on psychosocial aspects of cancer management, can address the unique care needs of patients with EO-GI cancers.
Inhibition of mPGES‐2 ameliorates NASH by activating NR1D1 via heme
Authors: Dandan Zhong, Jie Cai, Cheng Hu, Jingshuo Chen, Rumeng Zhang, Chenyu Fan, Shanshan Li, Hongxing Zhang, Zhou Xu, Zhanjun Jia, Dong Guo, Ying Sun
Journal: Hepatology (2022)

Background and Aims: Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase‐2 (mPGES‐2) was originally discovered as a prostaglandin E 2 (PGE 2 ) synthase; however, it does not produce PGE 2 in the liver. Moreover, the role of mPGES‐2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES‐2 in liver steatosis and steatohepatitis. Approach and Results: To evaluate the role of mPGES‐2 in NAFLD, whole‐body or hepatocyte‐specific mPGES‐2–deficient mice fed a high‐fat or methionine‐choline‐deficient diet were used. Compared with control mice, mPGES‐2–deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES‐2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl‐CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE 2 . Heme regulated the increased NR1D1 activity mediated by mPGES‐2 deficiency. Further, we confirmed the protective role of the mPGES‐2 inhibitor SZ0232 in NAFLD therapy. Conclusion: Our study indicates the pathogenic role of mPGES‐2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES‐2 inhibition in liver steatosis and steatohepatitis.
Precision Medicine in Biliary Tract Cancer
Authors: Aaron J. Scott, Reya Sharman, Rachna T. Shroff
Journal: Journal of Clinical Oncology (2022)

Precision medicine has become a dominant theme in the treatment of biliary tract cancers (BTCs). Although prognosis remains poor, technologies for improved molecular characterization along with the US Food and Drug Administration approval of several targeted therapies have changed the therapeutic landscape of advanced BTC. The hallmark of BTC oncogenesis is chronic inflammation of the liver and biliary tract regardless of the anatomical subtype. Subtypes of BTC correspond to distinct molecular characteristics, making BTC a molecularly heterogenous collection of tumors. Collectively, up to 40% of BTCs harbor a potentially targetable molecular abnormality, and the National Comprehensive Cancer Network guidelines recommend molecular profiling for all patients with advanced BTC. Use of circulating tumor DNA, immunohistochemistry, and next-generation sequencing continues to expand the utility for biomarker-driven management and molecular monitoring of BTC. Improving outcomes using biomarker-agnostic treatment for nontargetable tumors also remains a priority, and combinational treatment strategies such as immune checkpoint inhibition plus chemotherapy hold promise for this subgroup of patients.
Gene Expression Signatures for the Accurate Diagnosis of Peripheral T-Cell Lymphoma Entities in the Routine Clinical Practice
Authors: Catalina Amador, Alyssa Bouska, George Wright, Dennis D. Weisenburger, Andrew L. Feldman, Timothy C. Greiner, Waseem Lone, Tayla Heavican, Lynette Smith, Stefano Pileri, Valentina Tabanelli, German Ott, Andreas Rosenwald, Kerry J. Savage, Graham Slack, Won Seog Kim, Young Hyeh, Yuping Li, Gehong Dong, Joo Song, Sarah Ondrejka, James R. Cook, Carlos Barrionuevo, Soon Thye Lim, Choon Kiat Ong, Jennifer Chapman, Giorgio Inghirami, Philipp W. Raess, Sharathkumar Bhagavathi, Clare Gould, Piers Blombery, Elaine Jaffe, Stephan W. Morris, Lisa M. Rimsza, Julie M. Vose, Louis Staudt, Wing C. Chan, Javeed Iqbal
Journal: Journal of Clinical Oncology (2022)

Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis.We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays.In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen-derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners.We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.
Statistical Considerations for Analyses of Time-To-Event Endpoints in Oncology Clinical Trials: Illustrations with CAR-T Immunotherapy Studies
Authors: Yimei Li, Wei-Ting Hwang, Shannon L. Maude, David T. Teachey, Noelle V. Frey, Regina M. Myers, Allison Barz Leahy, Hongyan Liu, David L. Porter, Stephan A. Grupp, Pamela A. Shaw
Journal: Clinical Cancer Research (2022)

Abstract Chimeric antigen receptor T-cell (CAR-T) therapy is an exciting development in the field of cancer immunology and has received a lot of interest in recent years. Many time-to-event (TTE) endpoints related to relapse, disease progression, and remission are analyzed in CAR-T studies to assess treatment efficacy. Definitions of these TTE endpoints are not always consistent, even for the same outcomes (e.g., progression-free survival), which often stems from analysis choices regarding which events to consider as part of the composite endpoint, censoring or competing risk in the analysis. Subsequent therapies such as hematopoietic stem cell transplantation are common but are not treated the same in different studies. Standard survival analysis methods are commonly applied to TTE analyses but often without full consideration of the assumptions inherent in the chosen analysis. We highlight two important issues of TTE analysis that arise in CAR-T studies, as well as in other settings in oncology: the handling of competing risks and assessing the association between a time-varying (post-infusion) exposure and the TTE outcome. We review existing analytical methods, including the cumulative incidence function and regression models for analysis of competing risks, and landmark and time-varying covariate analysis for analysis of post-infusion exposures. We clarify the scientific questions that the different analytical approaches address and illustrate how the application of an inappropriate method could lead to different results using data from multiple published CAR-T studies. Codes for implementing these methods in standard statistical software are provided.
Moving the Needle on Precision Medicine in Pancreatic Cancer
Authors: Grainne M. O'Kane, Maeve A. Lowery
Journal: Journal of Clinical Oncology (2022)

The management of pancreatic ductal adenocarcinoma (PDAC) has posed a considerable challenge for decades, with incidence and mortality rates almost mirroring each other. Despite this, a deeper understanding of the complex biology inherent to PDAC has provided a roadmap for a more precise approach to treatment. PDAC deficient in homologous recombination repair and mismatch repair is a subgroup that should be identified in the clinic for a targeted approach. In addition, KRAS wild-type PDAC, occurring in approximately 10% of patients, is enriched in highly actionable alterations including fusions, underscoring the importance of integrative germline and somatic sequencing. Comprehensive sequencing efforts over the past decade have documented genomic- and transcriptomic-based classifiers, with the latter emerging as two main subtypes: the classical and basal-like, which are now being evaluated in clinical trials. Together with promising, innovative strategies to target KRAS mutations and their pleotropic effects, a new era of precision medicine in PDAC is on the horizon.
When I use a word . . . . Too much medicine
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

The popularity of responsible investing has extended to the fixed-income and liquidity-management fields in recent years. Incorporating environmental, social, and governance (ESG) issues in cash investment decisions makes sense as part of overall credit risk management. In addition to challenges related to disclosure, criteria, measure, and verification, liquidity portfolios face unique challenges in the areas of relevance, concentration, short-termism, and transparency. In this article, the author describes ESG considerations for institutional liquidity investors and explains that rather than buying into a strategy with an ESG label, institutional liquidity investors should engage their managers to include ESG issues in general credit evaluation and monitoring to improve risk management. <b>TOPICS:</b>ESG investing, portfolio theory, portfolio construction <b>Key Findings</b> • The popularity of responsible investing has extended to the fixed-income and liquidity-management fields in recent years. Incorporating environmental, social, and governance (ESG) issues in cash investment decisions makes sense as part of overall credit risk management. • In addition to challenges related to disclosure, criteria, measure, and verification, liquidity portfolios face unique challenges in the areas of relevance, concentration, short-termism, and transparency. • Rather than buying into a strategy with an ESG label, the author explains that institutional liquidity investors should engage their managers to include ESG issues in general credit evaluation and monitoring to improve risk management.
Amplified <i>EPOR</i>/<i>JAK2</i> Genes Define a Unique Subtype of Acute Erythroid Leukemia
Authors: June Takeda, Kenichi Yoshida, Masahiro M. Nakagawa, Yasuhito Nannya, Akinori Yoda, Ryunosuke Saiki, Yotaro Ochi, Lanying Zhao, Rurika Okuda, Xingxing Qi, Takuto Mori, Ayana Kon, Kenichi Chiba, Hiroko Tanaka, Yuichi Shiraishi, Ming-Chung Kuo, Cassandra M. Kerr, Yasunobu Nagata, Daisuke Morishita, Nobuhiro Hiramoto, Akira Hangaishi, Hideyuki Nakazawa, Ken Ishiyama, Satoru Miyano, Shigeru Chiba, Yasushi Miyazaki, Toshiyuki Kitano, Kensuke Usuki, Nobuo Sezaki, Hisashi Tsurumi, Shuichi Miyawaki, Jaroslaw P. Maciejewski, Takayuki Ishikawa, Kazuma Ohyashiki, Arnold Ganser, Michael Heuser, Felicitas Thol, Lee-Yung Shih, Akifumi Takaori-Kondo, Hideki Makishima, Seishi Ogawa
Journal: Blood Cancer Discovery (2022)

Abstract Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome, whole-exome, and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains and amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having &amp;gt;80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains and amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL. Significance: This study reveals the major role of gains, amplifications, and mutations of EPOR and JAK2 in the pathogenesis of pure erythroleukemia. Their frequent response to ruxolitinib in patient-derived xenograft and cell culture models highlights a possible therapeutic role of JAK2 inhibition for erythroleukemia with EPOR/JAK2-involving lesions. This article is highlighted in the In This Issue feature, p. 369
More to Illich than overtreatment: his work is relevant as we reflect on pandemic management
Authors: Robert Dingwall
Journal: BMJ (2022)

<h3>Aims</h3> Intracranial aneurysms are treated with a variety of endovascular devices including coils, stents, and flow diverters. The mechanisms by which these devices result in aneurysm occlusion and subsequent healing have been the subject of significant research using various animal models. The murine Helsinki aneurysm model is a sidewall aneurysm created by the end-to-side anastomosis of a donor aortic graft onto the abdominal aorta of a recipient animal. The aim of this systematic review is to assess the efficacy of different endovascular devices for the treatment of the Helsinki model aneurysm. <h3>Methods</h3> We performed a systematic review of Pubmed in accordance with PRISMA guidelines, yielding eight studies detailing the results of endovascular treatment of this preclinical aneurysm model. Studies were included if they provided rates of complete aneurysm occlusion after treatment. <h3>Results</h3> In these studies, aneurysms were treated with coiling (n=81, 7 studies), stenting (n=67, 3 studies), stent-coiling (n=13, 1 study), and flow diversion (n=49, 2 studies). The results of each individual study are discussed with the goal of providing a measure of the relative efficacy of different endovascular devices for the treatment of this particular model aneurysm. We also pay special attention to insights into the mechanisms underlying aneurysm healing after different forms of endovascular therapy. <h3>Conclusion</h3> The data presented here may be useful to investigators attempting to demonstrate superiority of novel endovascular devices relative to previous device iterations using this preclinical model.
Immunologic Strategies in Pancreatic Cancer: Making <i>Cold</i> Tumors <i>Hot</i>
Authors: Nicholas A. Ullman, Paul R. Burchard, Richard F. Dunne, David C. Linehan
Journal: Journal of Clinical Oncology (2022)

The rising incidence and persistent dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for new effective systemic therapies. Immunotherapy has shown significant benefits in solid organ tumors, but has thus far been disappointing in the treatment of PDAC. There have been several promising preclinical studies, but translation into the clinic has proved to be challenging. This is likely a result of PDAC's complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Here, we summarize the mechanisms of immunosuppression within the PDAC tumor microenvironment and provide an up-to-date review of completed and ongoing clinical trials using various immunotherapy strategies.
Erasing the stigma: tattoos in the medical workforce
Authors: Bea Duric
Journal: BMJ (2022)

An emerging body of work has demonstrated that resting-state non-oscillatory, or aperiodic, 1/<i>f</i> neural activity is a functional and behaviorally relevant marker of cognitive function capacity. In the motor domain, previous work has only applied 1/<i>f</i> analyses to description of action coordination and performance. The value of aperiodic resting-state neural dynamics as a marker of individual visuomotor performance capacity remains unknown. Accordingly, the aim of this work was to investigate if individual 1/<i>f</i> intercept and slope parameters of aperiodic resting-state neural activity predict reaction time and perceptual sensitivity in an immersive virtual reality marksmanship task. The marksmanship task required speeded selection of target stimuli and avoidance of non-target stimuli selection. Motor and perceptual demands were incrementally increased across task blocks and participants performed the task across three training sessions spanning one week. When motor demands were high, steeper individual 1/<i>f</i> slope predicted shorter reaction time. This relationship did not change with practice. Increased 1/<i>f</i> intercept and a steeper 1/<i>f</i> slope were associated with higher perceptual sensitivity, measured as <i>d'</i>. However, this association was only observed under the highest levels of perceptual demand and only in the initial exposure to these conditions. Individuals with a lower 1/<i>f</i> intercept and a shallower 1/<i>f</i> slope demonstrated the greatest gains in perceptual sensitivity from task practice. These findings demonstrate that individual differences in motor and perceptual performance can be accounted for with resting-state aperiodic neural dynamics. The 1/<i>f</i> aperiodic parameters are most informative in predicting visuomotor performance under complex and demanding task conditions. In addition to predicting capacity for high visuomotor performance with a novel task, 1/<i>f</i> aperiodic parameters might also be useful in predicting which individuals might derive the most improvements from practice.
Deep brain stimulation for obsessive–compulsive disorder: a crisis of access
Authors: Veerle Visser-Vandewalle, Pablo Andrade, Philip E. Mosley, Benjamin D. Greenberg, Rick Schuurman, Nicole C. McLaughlin, Valerie Voon, Paul Krack, Kelly D. Foote, Helen S. Mayberg, Martijn Figee, Brian H. Kopell, Mircea Polosan, Eileen M. Joyce, Stephan Chabardes, Keith Matthews, Juan C. Baldermann, Himanshu Tyagi, Paul E. Holtzheimer, Chris Bervoets, Clement Hamani, Carine Karachi, Damiaan Denys, Ludvic Zrinzo, Patric Blomstedt, Matilda Naesström, Aviva Abosch, Steven Rasmussen, Volker A. Coenen, Thomas E. Schlaepfer, Darin D. Dougherty, Philippe Domenech, Peter Silburn, James Giordano, Andres M. Lozano, Sameer A. Sheth, Terry Coyne, Jens Kuhn, Luc Mallet, Bart Nuttin, Marwan Hariz, Michael S. Okun
Journal: Nature Medicine (2022)